Ring -substituted diphenylazetidinones, process for their preparation, medicaments comprising these compounds, and their use

ABSTRACT

One embodiment of the invention relates to compounds of the formula I,  
                 
 
     in which R1, R2, R3, R4, R5 and R6 have the meanings given in the specification. Other embodiments of the invention relate to physiologically acceptable salts of compounds of formula I, to processes for their preparation and to medicaments comprising these compounds. The compounds of the invention are suitable for use, for example, as hypolipidemics.

[0001] This application claims the benefit of the filing dates of GermanPatent Application Number 10227506.8, filed on Jun. 19, 2002, and U.S.Provisional Application No. 60/411,984, filed on Sep. 19, 2002, whichapplications are hereby incorporated by reference.

[0002] One embodiment of the invention relates to ring-substituteddiphenylazetidinones, their physiologically acceptable salts andderivatives having physiological functions.

[0003] Diphenylazetidinones (such as, for example, ezetimibe) and theiruse for treating hyperlipidemia, arteriosclerosis andhypercholesterolemia have already been described [cf. Drugs of theFuture 2000, 25(7):679-685 and U.S. Pat. No. 5,756,470].

[0004] One embodiment of the invention provides further compounds havinga therapeutically utilizable hypolipidemic action. For example, oneembodiment of the invention relates to novel compounds which, comparedto the compounds described in the prior art, are absorbed to a very lowextent. Very low absorption is to be understood as meaning an intestinalabsorption of less than about 10%, preferably less than or equal toabout 5%.

[0005] In one embodiment, absorption of the novel compounds may be lessthan that of ezetimibe.

[0006] In general, pharmaceutically active compounds that are absorbedto a low extent may have considerably fewer side-effects.

[0007] Accordingly, on emebodiment of the invention relates to compoundsof the formula I

[0008] wherein

[0009] R1, R2, R3, R4, R5, and R6, independently of one another, arechosen from:

[0010] (C₁-C₃₀)-alkylene-(LAG)_(q),

[0011] wherein at least one carbon atom of the alkylene radical isreplaced by aryl or heteroaryl radicals, which are unsubstituted orsubstituted one, two, or three times by R7; or by (C₃-C₁₀)-cycloalkyl orheterocycloalkyl radicals, which are unsubstituted or substituted one,two, three, or four times by R7,

[0012] and wherein at least one-carbon atom of the alkylene radical isoptionally replaced by a radical chosen from: —S(O)_(m)— (whereinm=0-2), —O—, —(C═O)—, —(C═S)—, —CH═CH—, —C≡C—, —N((C₁-C₆)-alkyl)-,—N(phenyl), —N((C₁-C₆)-alkyl-phenyl)-, —N(CO—(CH₂)₁₋₁₀—COOH)— and —NH—;

[0013] H, F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)-alkyl, CONH₂,CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, or O—(C₁-C₆)-alkyl, wherein the alkyl radical isunsubstituted or at least one hydrogen in the alkyl radical is replacedby fluorine;

[0014] SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂,S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl,SO—(CH₂)_(n)-phenyl, SO₂—(C₁-C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl, whereinn=0-6, and wherein the phenyl radical is unsubstituted or substitutedone or two times, each substituent chosen independently from: F, Cl, Br,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, or NH₂;

[0015] NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NH(C₁-C₇)-acyl, phenyl,or O—(CH₂)_(n)-phenyl, wherein n=0-6, wherein the phenyl ring isunsubstituted or substituted one, two, or three times, each substituentchosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, or CONH₂;

[0016] R7 is F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)-alkyl,CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, or O—(C₁-C₆)-alkyl, wherein the alkylradical is unsubstituted or at least one hydrogen in the alkyl radicalis replaced by fluorine;

[0017] PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂,S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl,SO—(CH₂)_(n)-phenyl, SO₂-(C₁-C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl, whereinn=0-6, and wherein the phenyl radical is unsubstituted or substitutedone or two times, each substituent chosen independently from: F, Cl, Br,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, or NH₂; or

[0018] C(NH)(NH₂), NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,NH(C₁-C₇)-acyl, phenyl, or O—(CH₂)_(n)-phenyl, wherein n=0-6, andwherein the phenyl ring is unsubstituted or substituted one, two, orthree times, each substituent chosen independently from: F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, orCONH₂;

[0019] wherein (LAG) is:

[0020] a sugar residue, disugar residue, trisugar residue, tetrasugarresidue; a sugar acid, an amino sugar;

[0021] an amino acid residue, an oligopeptide residue comprising 2 to 9amino acids; or

[0022] an acyclic, mono-, di- or tricyclic trialkylammonium radical, anacyclic mono-, di- or tricyclic trialkylammoniumalkyl radical,—O—(SO₂)—OH; —(CH₂)₀₋₁₀—SO₃H; —(CH₂)₀₋₁₀—P(O)(OH)₂,—(CH₂)C₀₋₁₀—O—P(O)(OH)₂, —(CH₂)₀₋₁₀—COOH, —(CH₂)₀₋₁₀—C(═NH)(NH₂);—(CH₂)₀₋₁₀—C(═NH)(NHOH); or —NR8-C(═NR9)(NR10R11);

[0023] wherein q=1-5 and wherein R8, R9, R10 and R11, independently ofone another are chosen from H, (C₁-C₆)-alkyl, phenyl,(C₁-C₆)-alkyl-phenyl, or (C₃-C₈)-cycloalkyl),

[0024] and wherein at least one of the radicals R1 to R6 must have themeaning:

[0025] (C₁-C₃₀)-alkylene-(LAG)_(q), wherein at least one carbon atom ofthe alkylene radical is replaced by: aryl or heteroaryl radicals, whichare unsubstituted or substituted one, two, or three times by R7; or by(C₃-C₁₀)-cycloalkyl or heterocycloalkyl radicals, which areunsubstituted or substituted one, two, three, or four times by R7; andwherein at least one carbon atom of the alkylene radical is optionallyreplaced by a radical chosen from: —S(O)_(m)— (wherein m=0-2), —O—,—(C═O)—, —(C═S)—, —CH═CH—, —C≡C—, —N((C₁-C₆)-alkyl)-, —N(phenyl)-,—N((C₁-C₆)-alkyl-phenyl)-, —N(CO—(CH₂)₁₋₁₀—COOH)— and —NH—;

[0026] or a physiologically acceptable salt thereof, in anystereoisomeric form, or a mixture of any such compounds in any ratio.

[0027] In one embodiment of the invention, at least one of the radicalsR1 to R6 in the compounds of the formula I has the meaning(C₁-C₃₀)-alkylene-(LAG)_(q), wherein q=1-5 and wherein at least onecarbon atom of the alkylene radical is replaced by: aryl or heteroarylradicals, which are unsubstituted or substituted one, two, or threetimes by R7; or by (C₃-C₁₀)-cycloalkyl or heterocycloalkyl radicals,which are unsubstituted or substituted one, two, three, or four times byR7, and wherein at least one carbon atom of the alkylene radical isoptionally replaced by a radical chosen from: —S(O)_(m)— (whereinm=0-2), —O—, —(C═O)—, —(C═S)—, —CH═CH—, —C≡C—, —N((C₁-C₆)-alkyl)-,—N(phenyl)-, —N((C₁-C₆)-alkyl-phenyl)-, —N(CO—(CH₂)₁₋₁₀—COOH)— and —NH—.

[0028] In another embodiment of the invention, one of the radicals R1 orR3 in the compounds of the formula I has the meaning(C₁-C₃₀)-alkylene-(LAG), wherein at least one carbon atom of thealkylene radical is replaced by aryl or heteroaryl radicals, which areunsubstituted or substituted one, two, or three times by R7; or by(C₃-C₁₀)-cycloalkyl or heterocycloalkyl radicals, which areunsubstituted or substituted one, two, or three times by R7 and whereinat least one carbon atom of the alkylene radical is optionally replacedby a radical chosen from: —S(O)_(m)— (wherein m=0-2), —O—, —(C═O)—,—N(CH₃)—, —N(phenyl)-, —N(CO—(CH₂)₁₋₁₀—COOH)— and —NH—.

[0029] In another embodiment of the invention, one of the radicals R1 orR3 in the compounds of the formula I has the meaning—(CH₂)₀₋₁—NH—(C═O)₀₋₁—(C₀-C₂₅)-alkylene-(C═O)₀₋₁—N(R13)0-1-(LAG) or—(CH₂)₀₋₁—(C═O)₀₋₁—NH—(C₀-C₂₅)-alkylene-(C═O)₀₋₁—N(R13)₀₋₁-(LAG);wherein at least one carbon atom of the alkylene radical is replaced by:aryl or heteroaryl radicals, which are unsubstituted or substituted one,two, or three times by R7; or by (C₃-C₁₀)-cycloalkyl or heterocycloalkylradicals, which are unsubstituted or substituted one, two, or threetimes by R7; and wherein at least one carbon atom of the alkyleneradical is optionally replaced by a radical chosen from: oxygen atoms,NH, N(CH₃) and SO₂ , and wherein R13 represents H or CH₃.

[0030] In another embodiment of the invention, the group LAG in any ofthe radicals R1 to R6 in the compounds of the invention is a monosugarresidue, an acyclic mono-, di- or tricyclic trialkylammoniumalkylradical, a sulfonic acid or a carboxylic acid.

[0031] An aryl radical is to be understood as meaning a phenyl,naphthyl, biphenyl, tetrahydronaphthyl, alpha or beta-tetralone, indanylor indan-1-onyl radical.

[0032] A heteroaryl radical is to be understood as meaning a pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, pyridazin-3-onyl, pyrrolyl,imidazolyl, pyrazolyl, 1,2,4-triazolyl, indolyl, benzimidazolyl,thienyl, furyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl radical.

[0033] Heterocycloalkyl radicals are to be understood as meaning(C₃-C₁₀)-cycloalkyl radicals in which at least one and up to threecarbon atoms independently of one another are replaced by NR8, O orS(O)_(m), wherein m=0-2. Examples include the azetidinyl, pyrrolidinyl,piperidinyl, morpholinyl, 1,4-dioxanyl, tetrahydrofuryl, piperazinyl orthiepanyl radicals.

[0034] An acyclic trialkylammonium radical is to be understood asmeaning the following group

[0035] in which n=0 to 10 and Alk₁ and Alk₂, independently of oneanother, each denote a straight-chain or branched alkyl radical having 1to 20 carbon atoms.

[0036] An acyclic trialkylammoniumalkyl radical is to be understood asmeaning the following group

[0037] in which n=0 to 10 and Alk₁, Alk₂, Alk₃, independently of oneanother, each denote a straight-chain or branched alkyl radical having 1to 20 carbon atoms.

[0038] A mono-, di- or tricyclic trialkylammonium radical is to beunderstood as meaning, for example, radicals such as

[0039] wherein n, m and p, independently of one another, can be 0-10 andwherein one or more CH₂ groups, independently of one another, may bereplaced by O, S(O)_(m) (wherein m may be 0-2), NH, N—(C₁-C₁₀)-alkyl,N-phenyl or N—CH₂-phenyl.

[0040] A mono-, di- or tricyclic trialkylammoniumalkyl radical is to beunderstood as meaning, for example, radicals such as

[0041] wherein n, m and p, independently of one another, can be 0-10 andwherein one or more CH₂ groups independently of one another may bereplaced by O, S(O)_(m) (wherein m may be 0-2), NH, N—(C₁-C₁₀)-alkyl,N-phenyl or N—CH₂-phenyl and Alk₁ is a straight-chain or branched alkylradical having 1 to 20 carbon atoms.

[0042] Other than in the operating examples, or where otherwiseindicated, all numbers expressing quantities of ingredients, reactionconditions, and so forth used in the specification and claims are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the present specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldbe construed in light of the number of reported significant digits andby applying ordinary rounding techniques.

[0043] Notwithstanding that the numerical ranges and parameters settingforth the broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contain certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

[0044] Owing to their increased solubility in water, pharmaceuticallyacceptable salts are often more suitable for medical applications thanthe parent compounds. These salts generally have a pharmaceuticallyacceptable anion or cation. Examples of suitable pharmaceuticallyacceptable acid addition salts of the compounds according to theinvention include salts of inorganic acids, such as hydrochloric acid,hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid,sulfonic acid and sulfuric acid, and of organic acids, such as aceticacid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonicacid, fumaric acid, gluconic acid, glycolic acid, isothionic acid,lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonicacid, succinic acid, p-toluenesulfonic acid, tartaric acid andtrifluoroacetic acid, for example. An example of an acceptable salt ofthe compounds of the invention is the chloride salt. Examples ofsuitable pharmaceutically acceptable basic salts include ammonium salts,alkali metal salts (such as sodium and potassium salts) and alkalineearth metal salts (such as magnesium and calcium salts).

[0045] The scope of the invention also includes salts having apharmaceutically unacceptable anion, which salts may be usefulintermediates for preparing or purifying pharmaceutically acceptablesalts and/or for use in nontherapeutic, for example in vitro,applications.

[0046] Here, the term “derivative having physiological function” refersto any physiologically acceptable derivative of a compound according tothe invention, for example an ester, that is able, upon administrationto a mammal, for example a human, to form such a compound or an activemetabolite (directly or indirectly).

[0047] A further aspect of this invention includes prodrugs of thecompounds according to the invention. Such prodrugs can be metabolizedin vivo to give a compound according to the invention. These prodrugsmay or may not be active in their own right.

[0048] The compounds according to the invention can also be present invarious polymorphic forms, for example as amorphous and crystallinepolymorphous forms.

[0049] Accordingly, another aspect of the invention includes thepolymorphic forms of the compounds according to the invention.

[0050] Hereinbelow, all references to “compound(s) of the formula (I)”refer to a compound or compounds of the formula (I) as described above,and to their salts, solvates and derivatives having physiologicalfunction, as described herein.

[0051] The compounds of the formula I and their pharmaceuticallyacceptable salts and derivatives having physiological function areuseful medicaments for treating an impaired lipid metabolism, forexample, hyperlipidemia. The compounds of the formula I are alsosuitable for modulating the serum cholesterol concentration and forpreventing and treating arteriosclerotic manifestations.

[0052] As used herein,treating or treatment includes the treating of,for example, a patient inflicted with a disease or condition, as well asthe prevention, prophylaxis, or protective treatment of a patient.Treatment also includes treating a subject susceptible to or predisposedto developing a disease or condition, which could include patients inwhom the disease or condition has not yet presented, as well as patientsin whom the disease has been successfully treated but could redevelop orreoccur.

[0053] The compound(s) of the formula (I) can also be administered incombination with other active compounds.

[0054] The amount of a compound of the formula (I) required to achievethe desired biological effect depends on a number of factors, forexample on the specific compound chosen, on the intended use, on themode of administration and on the clinical condition of the patient. Ingeneral, the daily dose is in the range from 0.1 mg to 100 mg (typicallyfrom 0.1 mg to 50 mg) per day per kilogram of bodyweight, for example0.1-10 mg/kg/day. Tablets or capsules may contain, for example, from0.01 to 100 mg, typically from 0.02 to 50 mg. In the case ofpharmaceutically acceptable salts, the abovementioned weight data relateto the weight of the diphenylazetidinone-ion derived from the salt. Aneffective amount of a compound of the invention is an amount sufficientto bring about a desired effect. For example, in the context of treatingan impaired lipid metabolism, for instance hyperlipidemia, an effectiveamount of a compound of the invention would constitute an amountsufficient to bring about a beneficial change in the condition of thepatient. For the prophylaxis or therapy of the abovementionedconditions, the compounds of the formula (I) can be used by themselves,but they may also be present in the form of a pharmaceutical compositionwith an acceptable carrier. The carrier must of course be acceptable inthe sense that it is compatible with the other constituents of thecomposition and relatively speaking is not harmful to the health of thepatient. The carrier can be a solid or a liquid or both and may beformulated with the compound as an individual dose, for example as atablet, which can contain from 0.05% to 95% by weight of the activecompound. Further pharmaceutically active substances can also bepresent, including further compounds of the formula (I). Thepharmaceutical compositions according to the invention can be preparedby one of the known pharmaceutical methods, which essentially consist inmixing the constituents with pharmacologically acceptable carriersand/or auxiliaries.

[0055] Pharmaceutical compositions according to the invention includethose which are suitable for oral or peroral (e.g. sublingual)administration, although the most suitable manner of administration isdependent in each individual case on the nature and severity of thecondition to be treated and on the type of the compound of the formula(I) used in each case. Coated formulations and coated delayed-releaseformulations are also included in the scope of the invention, asareacid-resistant and enteric formulations. Examples of suitable entericcoatings include cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropylmethylcellulose phthalate and anionic polymersof methacrylic acid and methyl methacrylate.

[0056] Suitable pharmaceutical compounds for oral administration can bepresent in separate units, such as, for example, capsules, cachets,lozenges or tablets, which in each case contain a specific amount of thecompound of the formula (I); as a powder or granules; as a solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. As already mentioned, these compositions can beprepared according to any suitable pharmaceutical method that includes astep in which the active compound and the carrier (which can consist ofone or more additional constituents) are brought into contact. Ingeneral, the compositions are prepared by uniform and homogeneous mixingof the active compound with a liquid and/or finely divided solidcarrier, after which the product, if necessary, is shaped. For example,a tablet can thus be prepared by pressing or shaping a powder orgranules of the compound, if appropriate with one or more additionalconstituents. Pressed tablets can be produced by tableting the compoundin free-flowing form, such as, for example, a powder or granules, ifappropriate mixed with a binder, lubricant, inert diluent and/or a(number of) surface-active/dispersing agent(s) in a suitable machine.Shaped tablets can be produced by shaping the pulverulent compoundmoistened with an inert liquid diluent in a suitable machine.

[0057] Pharmaceutical compositions suitable for peroral (sublingual)administration include lozenges which contain a compound of the formula(I) with a flavoring, customarily sucrose and gum arabic or tragacanth,and pastilles which include the compound in an inert base such asgelatin and glycerol or sucrose and gum arabic.

[0058] Other suitable other active compounds for the combinationpreparations include, but are not limited to:

[0059] all antidiabetics mentioned in Rote Liste 2001, Chapter 12. Theycan be combined with the compounds of the formula I according to theinvention to achieve a synergistically enhanced action. The activecompound combination can be administered either by separateadministration of the active compounds to the patient or in the form ofcombination preparations comprising a plurality of active compounds in apharmaceutical preparation.

[0060] Antidiabetics include insulin and insulin derivatives, such as,for example, Lantus® or HMR 1964, GLP-1 derivatives, such as, forexample, those disclosed by Novo Nordisk A/S in WO 98/08871, and oralhypoglycemic active compounds.

[0061] Examples of oral hypoglycemic active compounds includesulfonylureas, biguadines, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1agonists, potassium channel openers, such as, for example, thosedisclosed by Novo Nordisk A/S in WO 97/26265 and WO 99/03861, insulinsensitizers, inhibitors of liver enzymes involved in stimulatinggluconeogenesis and/or glycogenolysis, modulators of glucose uptake,compounds which modulate lipid metabolism, such as antihyperlipidemicactive compounds and antilipidemic active compounds, compounds thatreduce food intake, PPAR and PXR agonists and active compounds that acton the ATP-dependent potassium channel of the beta cells.

[0062] In one embodiment of the invention, the compounds of the formulaI are administered in combination with an HMGCoA reductase inhibitorsuch as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, or rosuvastatin.

[0063] In another embodiment of the invention, the compounds of theformula I are administered in combination with a cholesterol absorptioninhibitor, such as, for example, ezetimibe, tiqueside, or pamaqueside.

[0064] In another embodiment of the invention, the compounds of theformula I are administered in combination with a PPAR gamma agonist,such as, for example, rosiglitazone, pioglitazone, JTT-501, or GI262570.

[0065] In another embodiment of the invention, the compounds of theformula I are administered in combination with a PPAR alpha agonist,such as, for example, GW 9578, or GW 7647.

[0066] In another embodiment of the invention, the compounds of theformula I are administered in combination with a mixed PPAR alpha/gammaagonist, such as, for example, GW 1536, AVE 8042, AVE 8134, or AVE 0847.

[0067] In another embodiment of the invention, the compounds of theformula I are administered in combination with a fibrate, such as, forexample, fenofibrate, clofibrate, or bezafibrate.

[0068] In another embodiment of the invention, the compounds of theformula I are administered in combination with an MTP inhibitor, suchas, for example, Bay 13-9952, BMS-201038, or R-103757.

[0069] In another embodiment of the invention, the compounds of theformula I are administered in combination with a bile acid absorptioninhibitor, such as, for example, HMR 1453.

[0070] In another embodiment of the invention, the compounds of theformula I are administered in combination with a CETP inhibitor, suchas, for example, Bay 194789.

[0071] In another embodiment of the invention, the compounds of theformula I are administered in combination with a polymeric bile acidadsorber, such as, for example, cholestyramine, or colesolvam.

[0072] In another embodiment of the invention, the compounds of theformula I are administered in combination with an LDL receptor inducer,such as, for example, HMR1171, or HMR1586.

[0073] In another embodiment of the invention, the compounds of theformula I are administered in combination with an ACAT inhibitor, suchas, for example, avasimibe.

[0074] In another embodiment of the invention, the compounds of theformula I are administered in combination with an antioxidant, such as,for example, OPC-14117.

[0075] In another embodiment of the invention, the compounds of theformula I are administered in combination with a lipoprotein lipaseinhibitor, such as, for example, NO-1886.

[0076] In another embodiment of the invention, the compounds of theformula I are administered in combination with an ATP citrate lyaseinhibitor, such as, for example, SB-204990.

[0077] In another embodiment of the invention, the compounds of theformula I are administered in combination with a squalene synthetaseinhibitor, such as, for example, BMS-188494.

[0078] In another embodiment of the invention, the compounds of theformula I are administered in combination with a lipoprotein(a)antagonist, such as, for example, CI-1027 or nicotinic acid.

[0079] In another embodiment of the invention, the compounds of theformula I are administered in combination with a lipase inhibitor, suchas, for example, Orlistat.

[0080] In another embodiment of the invention, the compounds of theformula I are administered in combination with insulin.

[0081] In another embodiment, the compounds of the formula I areadministered in combination with a sulfonylurea, such as, for example,tolbutamide, glibenclamide, glipizide or gliclazide.

[0082] In another embodiment, the compounds of the formula I areadministered in combination with a biguanide, such as, for example,metformin.

[0083] In another embodiment, the compounds of the formula I areadministered in combination with a meglitinide, such as, for example,repaglinide.

[0084] In another embodiment, the compounds of the formula I areadministered in combination with a thiazolidinedione, such as, forexample, troglitazone, ciglitazone, pioglitazone, rosiglitazone, or thecompounds disclosed by Dr. Reddy's Research Foundation in WO 97/41097,for example5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

[0085] In another embodiment, the compounds of the formula I areadministered in combination with an α-glucosidase inhibitor, such as,for example, miglitol or acarbose.

[0086] In another embodiment, the compounds of the formula I areadministered in combination with an active compound that acts on theATP-dependent potassium channel of beta cells, such as, for example,tolbutamide, glibenclamide, glipizide, gliazide or repaglinide.

[0087] In another embodiment, the compounds of the formula I areadministered in combination with more than one of the abovementionedcompounds, for example in combination with a sulfonylurea and metformin,a sulfonylurea and acarbose, repaglinide and metformin, insulin and asulfonylurea, insulin and metformin, insulin and troglitazon, or insulinand lovastatin, etc.

[0088] In a further embodiment, the compounds of the formula I areadministered in combination with CART agonists, NPY agonists, MC3 andMC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists,CRF BP antagonists, urocortin agonists, β3-agonists, MCH(melanine-concentrating hormone) antagonists, CCK agonists, serotoninreuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HTagonists, bombesin agonists, galanin antagonists, growth hormone, growthhormone-releasing compounds, TRH agonists, decoupling protein 2 or 3modulators, leptin agonists, DA agonists (bromocriptine, doprexin),lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-βagonists.

[0089] In another embodiment of the invention, the further activecompound is leptin.

[0090] In another embodiment, the further active compound isdexamphetamine or amphetamine.

[0091] In another embodiment, the further active compound isfenfluramine or dexfenfluramine.

[0092] In another embodiment, the further active compound issibutramine.

[0093] In another embodiment, the further active compound is Orlistat.

[0094] In another embodiment, the further active compound is mazindol orphentermine.

[0095] In another embodiment, the compounds of the formula I areadministered in combination with fiber, for example insoluble fiber,such as, for example, Caromax®. The combination with Caromax® can beadministered in a single preparation or by separate administration ofcompounds of the formula I and Caromax®. Here, Caromax® can also beadministered in the form of food, such as, for example, in bakery goodsor muesli bars. Compared to the individual active compounds, thecombination of compounds of the formula I with Caromax® is, in additionto providing an enhanced action, also characterized by its improvedtolerability, for example with respect to the lowering of LDLcholesterol.

[0096] It goes without saying that each suitable combination of thecompounds according to the invention with one or more of the compoundsmentioned above and optionally one or more further pharmacologicallyactive substances is included in the scope of the present invention.

[0097] The scope of the invention also includes both, stereoisomermixtures of the formula I and the pure stereoisomers of the formula I,as well as diastereomer mixtures of compounds of the formula I and thepure diastereomers. The mixtures may, for example, be separated by knownchromatographic means.

[0098] One embodiment of the invention includes both, racemic andenantiomerically pure compounds of the formula I of the followingstructure:

[0099] Sugar residues are to be understood as meaning, for example,compounds derived from aldoses and ketoses that have 3 to 7 carbon atomsand that may belong to the D or the L series; also included are aminosugars, sugar alcohols or sugar acids. Glucose, mannose, fructose,galactose, ribose, erythrose, glycerolaldehyde, sedoheptulose,glucosamine, galactosamine, glucuronic acid, galacturonic acid, gluconicacid, galactonic acid, mannonic acid, glucamine,3-amino-1,2-propanediol, glucaric acid and galactaric acid may bementioned by way of example.

[0100] Disugars are saccharides composed of two sugar units. Di-, tri-or tetrasaccharides are formed by acetal-like binding of two or moresugars. Here, the bonds may be in the α- or β-form. Lactose, maltose andcellobiose may be mentioned by way of example.

[0101] If the sugar is substituted, the substitution may take place atthe hydrogen atom of an OH group of the sugar. allo-hydroxylysineN-methylvaline 3-hydroxyproline norvaline 4-hydroxyproline norleucineisodesmosine ornithine allo-isoleucine N-methylglycine

[0102] For abbreviating the amino acids, the conventional notation wasused (cf. Schröder, Lübke, The Peptides, Volume I, New York 1965, pagesXXII-XXIII; Houben-Weyl, Methoden der Organischen Chemie [Methods oforganic chemistry], Volume XV/1 and 2, Stuttgart 1974). The amino acidpGlu denotes pyroglutamyl, Nal denotes 3-(2-naphthyl)alanine, azagly-NH₂denotes a compound of the formula NH₂—NH—CONH₂ and D-Asp denotes the Dform of aspartic acid. According to their chemical nature, peptides areacid amides, and on hydrolysis they decompose into amino acids.

[0103] An oligopeptide is to be understood as meaning a peptideconstructed of 2 to 9 of the amino acids mentioned above.

[0104] Examples of suitable protective groups (see, for example, T. W.Greene, “Protective Groups in Organic Synthesis”) for amino acidsinclude:

[0105] Arg(Tos), Arg(Mts), Arg(Mtr), Arg(PMV), Asp(OBzl), Asp(OBut),Cys(4-MeBzl), Cys(Acm), Cys(SBut), Glu(Obzl), Glu(Obut), His(Tos),His(Fmoc), His(Dnp), His(Trt), Lys(Cl-Z), Lys(Boc), Met(O), Ser(Bzl),Ser(But), Thr(Bzl), Thr(But), Trp(Mts), Trp(CHO), Tyr(Br-Z), Tyr(Bzl) orTyr(But).

[0106] Examples of amino protective groups that may be used include thebenzyloxycarbonyl (Z) radical, which can be removed by catalytichydrogenation; the 2-(3,5-dimethyloxyphenyl)propyl(2)oxycarbonyl(Ddz) ortrityl (Trt) radical, which can be removed by weak acids; thet-butylcarbamate (BOC) radical, which can be removed by 3M hydrochloricacid; and the 9-fluorenylmethyloxycarbonyl (Fmoc) radical, which can beremoved using secondary amines.

[0107] Another embodiment of the invention relates to a process forpreparing diphenylazetidinone derivatives of formula I.

[0108] Y can be S, O, (C═O), (C═S), CH═CH, C≡C, N((C1-C6)-alkyl),N(phenyl), N((C1-C6)-alkyl-phenyl), N(CO—(CH2)1-10-COOH) or NH;

[0109] R12 can be H or, if Y═(C═O) or (C═S), then R12 can be OH;

[0110] W can, independently of Y, be an aryl or heteroaryl radical,unsubstituted, or mono-, di-, or trisubstituted; or a(C3-C10)-cycloalkyl or heterocycloalkyl radical, unsubstituted, ormono-, di-, tri-, or tetrasubstituted; or —S(O)_(m)— (wherein m=0-2),—O—, —(C═O)—, —(C═S)—, —CH═CH—, —C≡C—, —N((C1-C6)-alkyl)-, —N(phenyl),—N((C1-C6)-alkyl-phenyl)-, —N(CO—(CH2)1-10-COOH)— or —NH— or a bond;

[0111] v, x, y and z, independently of one another, can be 0 to 10.

[0112] In compound II, —(CH2)x-Y—R12 can alternatively also be attachedto one of the other two phenyl rings.

[0113] The process for preparing compounds of the formula I comprises,for example, reacting an amine of the formula II with an alkylating oracylating agent which, may carry a further functionality (for example inthe omega position), if appropriate in protected form. Thisfunctionality may be used (after deprotection) for attaching (LAG), forexample with the formation of ether, amine or amide bonds.

[0114] The examples below serve to illustrate the invention in moredetail, without limiting the invention to the products and embodimentsdescribed in the examples.

EXAMPLE I

[0115] 2,3,4,5,6-Pentahydroxyhexylamide of4-(4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoicacid (7):

[0116] a)3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyl-oxazolidin-2-one(1):

[0117] 27 g of3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2one, 13.6g of tert-butyldimethylsilyl chloride and 10.2 g of imidazole weredissolved in 36 ml of dimethylformamide and stirred at 60° C. for 90min. After the reaction ended, the mixture was dissolved in ethylacetate and extracted two times with water. The organic phase was driedover magnesium sulfate, filtered and concentrated under reducedpressure. This produced3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyloxazolidin-2-one(1) of molecular weight 471.65 (C26H34FNO4Si); MS (ESI): 340.28(MH+-HOSi(CH3)2C(CH3)3).

[0118] b)4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile(2):

[0119] 16.2 g of3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyloxazolidin-2-one(1) were dissolved in 350 ml of dichloromethane. 19.8 ml of Hüinig baseand 10.14 g of 4-[(4-methoxyphenylimino)methyl]benzonitrile were added,and the solution was cooled to −10° C. 8.52 ml of trimethylsilyltriflate were added to the cooled solution, and the mixture was stirredat −10° C. for 30 min. The solution was then cooled to −30° C., and 44ml of titanium tetrachloride solution were added. The reaction mixturewas stirred at a temperature ranging from −30 to −40° C. for 2 h. Thesolution was then allowed to warm to room temperature and the reactionsolution was washed successively with 200 ml of 2N sulfuric acid, 300 mlof 20% strength sodium hydrogen sulfite solution and sat. sodiumchloride solution. The organic phase was dried over magnesium sulfate,concentrated under reduced pressure, and the residue was purified onsilica gel using n-heptane/ethyl acetate 3/1. This produced4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile(2) of molecular weight 707.93 (C41H46FN3O5Si); MS (ESI): 590.51(MH+-C7H5N2).

[0120] c)4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile(3):

[0121] 13.2 g of4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile(2) were dissolved in 380 ml of methyl tert-butylether. 18.6 ml ofN,O-bis(trimethylsilyl)acetamide and 1.86 ml of a 1 M solution oftetrabutylammonium fluoride in tetrahydrofuran were added and themixture was stirred at room temperature for 2 h. After the reactionended, 10 ml of acetic acid were added, the reaction mixture wasconcentrated under reduced pressure and the residue was purified onsilica gel using toluene/ethyl acetate 50/1. This produced4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile(3) of molecular weight 544.75 (C32H37FN2O3Si); MS (ESI): 545.56 (M+H+).

[0122] d)4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile(4):

[0123] 3.5 g of4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile(3) were dissolved in 65 ml of tetrahydrofuran. 0.74 ml of acetic acidand 8.03 ml of a 1 M solution of tetrabutylammonium fluoride intetrahydrofuran were added and the mixture was stirred at roomtemperature for 2 h. Another 4.82 ml of the tetrabutylammonium fluoridesolution were then added, and the mixture was stirred at refluxtemperature for another 3 h. The cooled reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography using n-heptane/ethyl acetate 2/1. Thisproduced4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile(4) of molecular weight 430.48 (C26H23FN203); MS (ESI): 431.24 (M+H+).

[0124] e)1-(4-Aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one(5):

[0125] 1.22 g of4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4oxoazetidin-1-yl]-benzonitrile(4) were dissolved in 90 ml of ethanol. 10 ml of conc. ammonia solutionand an excess of Raney nickel were added, and the mixture was stirred at60° C. and a hydrogen pressure of 10 bar for 8 h. Overnight, thereaction mixture cooled to room temperature. The next day, the catalystwas removed, the filtrate was concentrated under reduced pressure andthe residue was purified by silica gel chromatography usingdichloromethane/methanol/ammonia solution 10/1/0.1. This produced1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one(5) of molecular weight 434.51 (C26H27FN203); MS (ESI): 418.2 (MH+-NH3).

[0126] f) 2,3,4,5,6-Pentahydroxyhexylamide of 4,4′-oxybisbenzoic acid(6):

[0127] At room temperature, 0.52 g of 4,4′-oxybisbenzoic acid and 0.36 gof D-glucamine were suspended in 10 ml of dry dimethylformamide. 0.31 gof HOBt and 0.39 g of EDC were added and the mixture was stirred at roomtemperature for 12 h. The reaction mixture was evaporated to dryness anddried under high vacuum. The residue was thoroughly titrated with water,the resulting suspension was filtered and the residue was titrated withmethanol and filtered again. The filtrate was concentrated to half ofits volume using a rotary evaporator, and the solution was cooled in anice bath. The resulting precipitate was filtered off with suction,washed with a little ice-cooled methanol and dried under reducedpressure. This produced 2,3,4,5,6-pentahydroxyhexylamide of4,4′-oxybisbenzoic acid (6) of molecular weight 421.40 (C20H23NO9); MS(ESI): 422.28 (MH+).

[0128] Examples of suitable protective groups for the hydroxyl groups ofthe sugars include: benzyl, acetyl, benzoyl, pivaloyl, trityl,tert-butyldimethylsilyl, benzylidene, cyclohexylidene or isopropylideneprotective groups.

[0129] The term “amino acids” or “amino acid residues” refers, forexample, to the stereoisomeric forms, i.e. the D or L forms, of, forexample, the following compounds: alanine glycine proline cysteinehistidine glutamine aspartic acid isoleucine arginine glutamic acidlysine serine phenylalanine leucine threonine tryptophan methioninevaline tyrosine asparagine 2-aminoadipic acid 2-aminoisobutyric acid3-aminoadipic acid 3-aminoisobutyric acid beta-alanine 2-aminopimelicacid 2-aminobutyric acid 2,4-diaminobutyric acid 4-aminobutyric aciddesmosine piperidine carboxylic acid 2,2-diaminopimelic acid6-aminocaproic acid 2,3-diaminopropionic acid 2-aminoheptanoic acidN-ethylglycine 2-(2-thienyl)glycine 3-(2-thienyl)alanine penicillaminesarcosine N-ethylasparagine N-methylisoleucine hydroxylysine6-N-methyllysine

[0130] g) 2,3,4,5,6-Pentahydroxyhexylamide of4-(4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoicacid (7):

[0131] 87 mg of the compound prepared under e) and 90 mg of the compoundprepared under f) were dissolved at room temperature in 3 ml of drydimethylformamide. 31 mg of HOBt and 39 mg of EDC were added and themixture was stirred at room temperature for 12 h. The reaction mixturewas evaporated to dryness under high vacuum and the residue was titratedwith dichloromethane, filtered off with suction, washed withdichloromethane and dried under reduced pressure. This produced the2,3,4,5,6-pentahydroxyhexylamide of4-(4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoicacid (7) with a molecular weight 837.90 (C46H48FN3O11); MS (ESI): 838,39(MH+).

EXAMPLE II

[0132] 2,3,4,5,6-Pentahydroxyhexylamide of4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoicacid (9):

[0133] a) 1-(4-Aminomethylphenyl)-3-(3-hydroxy-3-phenylpropyl)-4-phenylazetidin-2-one (8):

[0134] This compound was prepared as described above for1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one,except that3-[5-(tert-butyldimethylsilanyloxy)-5-phenylpentanoyl]-4-phenyloxazolidin-2-oneand 4-(benzylideneamino)benzonitrile were used. This produced1-(4-aminomethylphenyl)-3-(3-hydroxy-3-phenylpropyl)-4-phenylazetidin-2-one(8) of molecular weight 386.50 (C25H26N2O2); MS (ESI): 370.2 (MH+-NH3).

[0135] b) 2,3,4,5,6-Pentahydroxyhexylamide of4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoicacid (9):

[0136] The benzylamine from IIa was reacted with the2,3,4,5,6-pentahydroxyhexylamide of 4,4′-oxybisbenzoic acid from If asdescribed in Example I. This produced the2,3,4,5,6-pentahydroxyhexylamide of4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoicacid (9) of molecular weight 789.89 (C45H47N3O10); MS (ESI): 790.26(MH+).

EXAMPLE III

[0137] 2,3,4,5,6-Pentahydroxyhexylamide of4-(4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)4-oxoazetidin-1-yl]-benzylcarbamoyl}-benzyl)-benzoicacid (10):

[0138] The compound of Example III was obtained analogously to theprocedure of Example I, except that the 2,3,4,5,6-pentahydroxyhexylamideof diphenylmethane-4,4′-dicarboxylic acid was used. This produced the2,3,4,5,6-pentahydroxyhexylamide of4-(4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzylcarbamoyl}benzyl)benzoicacid (10) of molecular weight 835.93 (C47H50FN3O10); MS (ESI): 836.18(MH+).

EXAMPLE IV

[0139]1-[4-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octanebromide (13):

[0140] a)4-[4-(4-Bromomethylbenzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one(12):

[0141] 3.0 g of1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-azetidin-2-one(11) 7.0 g of 1,4-bisbromomethylbenzene and 5.0 g of potassium carbonatewere dissolved in 100 ml of dimethylformamide and stirred at roomtemperature for 90 min. After the reaction ended, the mixture wasdissolved in ethyl acetate and extracted two times with water. Theorganic phase was dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography (n-heptane/ethyl acetate). Yield 3.2 g of colorlesscrystals (12) of molecular weight 592.49 (C32H28BrF2NO3); MS (ESI):592.2 (MH+).

[0142] b)1-[4-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane bromide(13):

[0143] 180 mg of (12) and 300 mg of 1,4-diazabicyclo[2.2.2]octane(DABCO) were dissolved in 5 ml of toluene and stirred at 80° C. for 90min. After the reaction ended, the mixture was allowed to cool and thecolorless solid was filtered off with suction. This gave 195 mg ofproduct (13) of molecular weight 704.66 (C38H40BrF2N3O3); MS (ESI):624.30 (MH+).

EXAMPLE V

[0144]1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{4-[(2,3,4,5,6-pentahydroxyhexylamine)methyl]benzyloxy}phenyl)azetidin-2-one(14)

[0145] 60 mg of (12) and 150 mg of glucamine were dissolved in 5 ml ofdimethylformamide and stirred at 80° C. for 90 min. After the reactionended, the mixture was dissolved in ethyl acetate and extracted twotimes with water. The organic phase was dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by flash chromatography (methylene chloride/methanol/conc.ammonia 30/10/3). Yield 33 mg of a colorless solid (14) of molecularweight 692.76 (C38H42F2N2O8); MS (ESI): 693.5 (MH+).

EXAMPLE VI

[0146]1-[2-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octanebromide (16):

[0147] a)4-[4-(2-Bromomethylbenzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one(15):

[0148]1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-azetidin-2-one(11) was reacted with 1,2-bisbromomethylbenzene and potassium carbonateanalogously to Example IV, giving a colorless solid (15) of molecularweight 592.49 (C32H28BrF2NO3); MS (ESI): 592.2 (MH+).

[0149] b)1-[4-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octanebromide (16):

[0150] Compound (15) and DABCO were dissolved in toluene and reactedanalogously to Example IV, giving the product (16) as a colorless solidof molecular weight 704.66 (C38H40BrF2N3O3); MS (ESI): 624.30 (MH+).

EXAMPLE VII

[0151]1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{2-[(2,3,4,5,6-pentahydroxyhexylamine)methyl]benzyloxy}phenyl)azetidin-2-one(17):

[0152] Compound (15) and glucamine were dissolved in dimethylformamideand reacted analogously to Example V, giving the product (17) as acolorless solid of molecular weight 692.76 (C38H42F2N2O8); MS (ESI):693.5 (MH+).

EXAMPLE VIII

[0153]1-[3-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octanebromide (19):

[0154] a)4-[4-(3-Bromomethylbenzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one(18):

[0155]1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one(11) was reacted with 1,3-bisbromomethylbenzene and potassium carbonateanalogously to Example IV, giving a colorless solid (18) of molecularweight 592.49 (C32H28BrF2NO3); MS (ESI): 592.2 (MH+).

[0156] b)1-[3-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxymethyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octanebromide (19):

[0157] Compound (18) and DABCO were dissolved in toluene and reactedanalogously to Example IV, giving the product (19) as a colorless solidof molecular weight 704.66 (C38H40BrF2N3O3); MS (ESI): 624.30 (MH+).

EXAMPLE IX

[0158]1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{3-[(2,3,4,5,6-pentahydroxyhexylamine)methyl]benzyloxy}phenyl)azetidin-2-one(20):

[0159] Compound (18) and glucamine were dissolved in dimethylformamideand reacted analogously to Example V, giving the product (20) as acolorless solid of molecular weight 692.76 (C38H42F2N2O8); MS (ESI):693.5 (MH+).

EXAMPLE X

[0160]1-[4′-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-oxoazetidin-2-yl}phenoxymethyl)biphenyl-4-ylmethyl]-4-aza-1-azoniabicyclo[2.2.2]octanebromide (22):

[0161] a)4-[4-(4′-Bromomethylbiphenyl-4-ylmethoxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one(21):

[0162]1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-azetidin-2-one(11) was reacted with 4,4′-bisbromomethylbiphenyl and potassiumcarbonate analogously to Example IV, giving a colorless solid (21) ofmolecular weight 668.54 (C38H32BrF2NO3); MS (ESI): 668.1 (MH+).

[0163] b)1-[4′-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxymethyl)biphenyl-4-ylmethyl]-4-aza-1-azoniabicyclo[2.2.2]octanebromide (22):

[0164] Compound (21) and DABCO were dissolved in toluene and reactedanalogously to Example IV, giving the product (22) as a colorless solidof molecular weight 780.76 (C44H44BrF2N3O3); MS (ESI): 700.3 (MH+).

EXAMPLE XI

[0165]1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-{4′-[(2,3,4,5,6-pentahydroxyhexylamine)-methyl]-biphenyl-4-ylmethoxy}-phenyl)-azetidin-2-one(23):

[0166] Compound (21) and glucamine were dissolved in dimethylformamideand reacted analogously to Example V, giving the product (23) as acolorless solid of molecular weight 768.86 (C44H46F2N2O8); MS (ESI):769.3 (MH+).

EXAMPLE XII

[0167]1-(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-phenoxymethyl}-benzyl)-4-aza-1-azoniabicyclo[2.2.2]octanebromide (26):

[0168] a)3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-azetidin-2-one(24):

[0169] This compound was prepared as described above for1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one(steps a, b, c, and d), except that4-[(4-methoxybenzylidene)-amino]-phenol was used. This produced3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-azetidin-2-one(24) of molecular weight 421.47 (C25H24FNO4); MS (ESI): 422.2 (MH+).

[0170] b)1-[4-(4-bromomethylbenzyloxy)-phenyl]-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one(25):

[0171]3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-azetidin-2-onewas reacted with 1,4-bisbromomethylbenzene and potassium carbonateanalogously to Example IV, giving a colorless solid (25) of molecularweight 604.52 (C33H31BrFNO4); MS (ESI): 605.2 (MH+).

[0172] c)1-(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-phenoxymethyl}-benzyl)-4-aza-1-azoniabicyclo[2.2.2]octanebromide (26):

[0173] Compound (25) and DABCO were dissolved in toluene and reactedanalogously to Example IV, giving the product (26) as a colorless solidof molecular weight 716.70 (C39H43BrFN3O4); MS (ESI): 636.3 (MH+).

EXAMPLE XIII

[0174]3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-1-(4-{4-[(2,3,4,5,6-pentahydroxyhexylamine)-methyl]-benzyloxy}-phenyl)-azetidin-2-one(27):

[0175] Compound (25) and glucamine were dissolved in dimethylformamideand reacted analogously to Example V, giving the product (27) as acolorless solid of molecular weight 704.80 (C39H45FN2O9); MS (ESI):705.31 (MH+).

EXAMPLE XIV

[0176]1-[4-(4-{3-[1-(4-Fluorophenyl)-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl]-1-hydroxypropyl}-phenoxymethyl)-benzyl]-4-aza-1-azoniabicyclo[2.2.2]octanebromide (30):

[0177] a)1-(4-Fluorophenyl)-3-[3-hydroxy-3-(4-hydroxyphenyl)-propyl]-4-(4-methoxyphenyl)-azetidin-2-one(28):

[0178] This compound was prepared as described above for1-(4aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one,except that3-[5-(4-hydroxyphenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one and(4-fluorophenyl)-(4-methoxybenzylidene)-amine were used. This produced1-(4-fluorophenyl)-3-[3-hydroxy-3-(4-hydroxyphenyl)-propyl]-4-(4-methoxyphenyl)-azetidin-2-one(28) of molecular weight 421.47 (C25H24FNO4); MS (ESI): 422.2 (MH+).

[0179] b)3-{3-[4-(4-Bromomethylbenzyloxy)-phenyl]-3-hydroxypropyl}-1-(4-fluorophenyl)-4-(4-methoxyphenyl)-azetidin-2-one(29):

[0180]1-(4-Fluorophenyl)-3-[3-hydroxy-3-(4-hydroxyphenyl)-propyl]-4-(4-methoxyphenyl)-azetidin-2-onewas reacted with 1,4-bisbromomethylbenzene and potassium carbonateanalogously to Example IV, giving a colorless solid (29) of molecularweight 604.52 (C33H31BrFNO4); MS (ESI): 605.2 (MH+).

[0181] c)1-[4-(4-{3-[1-(4-Fluorophenyl)-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl]-1-hydroxypropyl}-phenoxymethyl)-benzyl]-4-aza-1-azoniabicyclo[2.2.2]octanebromide (30):

[0182] Compound (29) and DABCO were dissolved in toluene and reactedanalogously to Example IV, giving the product (30) as a colorless solidof molecular weight 716.70 (C39H43BrFN3O4); MS (ESI): 636.3 (MH+).

EXAMPLE XV

[0183]1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-4-aza-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (35):

[0184] a) 1-(4-Carboxymethylbenzyl)-4-aza-1-azoniabicyclo[2.2.2]octanebromide (31):

[0185] At 70° C., 1.0 g of (3-bromomethylphenyl) acetic acid in 5 ml ofdimethyl sulfoxide were added to a solution of 1.5 g of1,4-diazabicyclo[2.2.2]octane in 10 ml of dimethyl sulfoxide. After 1 h,100 ml of water were added and the mixture was freeze-dried. The residuewas digested with acetone. The residue contained the product ofmolecular weight 261.35 (cation: C15H21N2O2+); MS (ESI) 261.1 (M+).

[0186] b)4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-pentyl]-benzonitrile(32):

[0187] Under argon, 2.5 g of3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one weredissolved in 30 ml of dichloromethane. 3.9 g of4-[(4-fluorophenylimino)-methyl]-benzonitrile were added and the mixturewas cooled to −10° C. 6.4 ml of diisopropylethylamine and, over a periodof 30 min, 4.05 ml of trimethylsilyl chloride were added to this mixtureso that the temperature did not exceed −5° C. The mixture was stirred atthis temperature for 1 additional hour and then cooled to −25° C. 0.8 mlof titanium tetrachloride were then added slowly. The dark mixture wasstirred at a temperature ranging from −25 to −30° C. overnight and thendecomposed using 35 ml of a 7 percent strength solution of tartaricacid. The solution was then stirred at room temperature for anotherhour. 15 ml of a 20 percent strength solution of sodium bicarbonate werethen added, and the mixture was again stirred for 1 hour. Followingphase separation, the organic phase was washed with 30 ml of water,dried over magnesium sulfate and concentrated to about 10 ml. Followingthe addition of 2 ml of bistrimethylsilylacetamide, the mixture washeated at reflux for 30 min and then concentrated under reducedpressure. The residue was crystallized using ethyl acetate/heptane. Theproduct was filtered off with suction and dried under reduced pressure.This gave the product of molecular weight 653.81 (C37H37F2N3O4Si); MS(ESI+): 654.3 (M+H+), 582.2 (M+H+-Si(CH3)3).

[0188] c){1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile(33):

[0189] 2 g of4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-pentyl]-benzonitrilewere dissolved in 20 ml of methyltert-butyl ether and, together with 100mg of tetrabutylammonium fluoride trihydrate and 1.3 ml ofbistrimethylsilyl acetamide, heated at 40° C. for about 1 h. Thereaction was monitored by thin-layer chromatography. After the reactionended, 0.2 ml of glacial acetic acid were initially added and themixture was stirred for 30 min and then concentrated. 20 ml of a mixtureof isopropanol/2N sulfuric acid=10:1 were added to the residue, and themixture was stirred for 1 hour. Following addition of a spatula tip ofsolid sodium bicarbonate, the mixture was again concentrated underreduced pressure. The residue was taken up in ethyl acetate and theorganic phase was washed with water and dried. The residue was, afterremoval of the solvent, purified by column chromatography (SiO2,CH2Cl2/methanol=100:1). This gave the product of molecular weight 418.45(C25H20F2N2O2); MS (DCI+): 419 (M+H+).

[0190] d)4-(4-Aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one(34):

[0191] 200 mg of{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrilewere dissolved in 20 ml of ethanol and, with 0.5 ml of conc. ammonia,hydrogenated over Raney nickel at a hydrogen pressure of 75 bar and at25° C. for 30 hours. The catalyst was filtered off with suction, themixture was concentrated under reduced pressure and the residue waspurified by column filtration (SiO₂, CH₂Cl₂/methanol/conc.NH₃=100:10:1). This gives the product of molecular weight 422.5(C25H22F2N2O2); MS (DCI+): 423 (M+H+), 405 (M+H+-H2O).

[0192] e)1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-4-aza-1-azonia-bicyclo[2.2.2]octane;trifluoroacetate (35):

[0193] A solution of 70 mg4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one,and 23 μl of triethylamine in 0.5 ml of dimethylformamide were added toa solution of 84 mg of1-(4-carboxymethylbenzyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide, 64μl of diisopropylcarbodiimide and 56 mg of hydroxybenzotriazole in 2 mlof dimethylformamide. The mixture was stirred at room temperature for 12h. The reaction solution was concentrated and separated by HPLC (KnauerEurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile(0.1% trifluoroacetic acid)=80/20→10/90). This gave the product ofmolecular weight 665.81 (cation: C40H43F2N4O3); MS (ESI) 665.33 (M+).

EXAMPLE XVI

[0194]1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (37):

[0195] a) 1-(4-Carboxymethylbenzyl)-1-azoniabicyclo[2.2.2]octane bromide(36):

[0196] The synthesis was carried out analogously to Example XVa),starting with 1.67 g of 1-azabicyclo[2.2.2]octane. This gave the productof molecular weight 260.36 (cation: C16H22N1O2+); MS (ESI) 260.1 (M+).

[0197] b)1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (37):

[0198] The synthesis was carried out analogously to Example XVe),starting with 70 mg of4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-oneand 85 mg of 1-(4-carboxymethylbenzyl)-1azoniabicyclo[2.2.2]octanebromide. This gave the product of molecular weight 664.82 (cation:C41H44F2N3O3+); MS (ESI) 664.33 (M+).

EXAMPLE XVII

[0199]1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4-dimethylpiperazin-1-iumtrifluoroacetate (39):

[0200] a) 1-(4-Carboxymethylbenzyl)-1,4-dimethylpiperazin-1-ium bromide(38):

[0201] The synthesis was carried out analogously to Example XVa),starting with 1.02 ml of 1,4-dimethylpiperazine. This gave the productof molecular weight 263.36 (cation: C15H23N2O2+); MS (ESI) 263.1 (M+).

[0202] b)1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4dimethyl-piperazin-1-iumtrifluoroacetate (39):

[0203] The synthesis was carried out analogously to Example XVe),starting with 70 mg of4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-oneand 86 mg of 1-(4-carboxymethylbenzyl)-1,4-dimethylpiperazin-1-iumbromide. This gave the product of molecular weight 667.82 (cation:C40H45F2N4O3+); MS (ESI) 667.34 (M+).

EXAMPLE XVIII

[0204]4-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-4-methylmorpholin-4-iumtrifluoroacetate (41):

[0205] a) 4-(4-Carboxymethylbenzyl)-4-methylmorpholin-4-ium bromide(40):

[0206] The synthesis was carried out analogously to Example XVa),starting with 1.65 ml of N-methylmorpholine. This gave the product ofmolecular weight 250.32 (cation: C14H20N1O3+); MS (ESI) 250.1 (M+).

[0207] b)4-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-4-methylmorpholin-4-iumtrifluoroacetate (41):

[0208] The synthesis was carried out analogously to Example XVe),starting with 70 mg of4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-oneand 82 mg of 4-(4-carboxymethylbenzyl)-4-methylmorpholin-4-ium bromide.This gave the product of molecular weight 654.78 (cation:C39H42F2N3O4+); MS (ESI) 654.31 (M+).

EXAMPLE XIX

[0209]1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4,7-trimethyl[1,4,7]triazonan-1-iumtrifluoroacetate (43):

[0210] a)1,4,7-Trimethyl-1-[4-(2-oxopropyl)-benzyl]-[1,4,7]triazonan-1-iumbromide (42):

[0211] The synthesis was carried out analogously to Example XVa),starting with 500 mg of 1,4,7-trimethyl-[1,4,7]triazonane. This gave theproduct of molecular weight 321.47 (cation: C18H31N3O2+); MS (ESI) 321.2(M+).

[0212] b)1-{4-[(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)-methyl]-benzyl}-1,4,7-trimethyl-[1,4,7]triazonan-1-iumtrifluoroacetate (43):

[0213] The synthesis was carried out analogously to Example XVe)starting with 70 mg of4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-oneand 200 mg of1,4,7-trimethyl-1-[4-(2-oxopropyl)-benzyl]-[1,4,7]triazonan-1-iumbromide. This gave the product of molecular weight 724.92 (cation:C40H45F2N4O3+); MS (ESI) 724.40 (M+).

EXAMPLE XX

[0214]1-[4-({4-[3-(3-Hydroxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yl]-benzylcarbamoyl}-methyl)-benzyl]-4-aza-1-azoniabicyclo[2.2.2]octanetrifluoroacetate (44):

[0215] The synthesis was carried out analogously to Example XVe),starting with 60 mg of1-(4-aminomethylphenyl)-3-(3-hydroxy-3-phenylpropyl)-4-phenylazetidin-2-one(8) and 82 mg of1-(4-carboxymethylbenzyl)-4-aza-1-azoniabicyclo[2.2.2]octane bromide.This gave the product of molecular weight 629.83 (cation:C40H45F2N4O3+); MS (ESI) 629.35 (M+).

EXAMPLE XXI

[0216]N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-oxoazetidin-2-yl}-benzyl)-2-{4-[(2,3,4,5,6-pentahydroxyhexylamino)-methyl]-phenyl}-acetamide(46):

[0217] a) {4-[(2,3,4,5,6-Pentahydroxyhexylamino)-methyl]-phenyl}-aceticacid (45):

[0218] The synthesis was carried out analogously to Example XVa),starting with 989 mg of 6-aminohexane-1,2,3,4,5-pentaol. This gave theproduct of molecular weight 329.35 (C15H23N1O7); MS (ESI) 330.2 (M +H+).

[0219] b)N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzyl)-2-{4-[(2,3,4,5,6-pentahydroxyhexylamino)-methyl]-phenyl}-acetamide(46):

[0220] The synthesis was carried out analogously to Example XVe),starting

[0221] 70 mg of4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-oneand 110 mg of{4-[(2,3,4,5,6-pentahydroxyhexylamino)-methyl]-phenyl}-acetic acid. Thisgave the product of molecular weight 733.82 (C40H45F2N3O8+); MS (ESI)734.32 (M +H+).

EXAMPLE XXII

[0222]N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzyl)-2-(4-{[methyl-(2,3,4,5,6-pentahydroxyhexyl)-amino]-methyl}-phenyl)-acetamide(48):

[0223] a)(4-{[Methyl-(2,3,4,5,6-pentahydroxyhexyl)-amino]-methyl}-phenyl)-aceticacid (47):

[0224] The synthesis was carried out analogously to Example XVa),starting with 1.06 g of 6-methylaminohexane-1,2,3,4,5-pentaol. This gavethe product of molecular weight 343.38 (C16H25N1O7); MS (ESI) 344.2(M+H+).

[0225] b)N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-oxoazetidin-2-yl}-benzyl)-2-(4-{[methyl-(2,3,4,5,6-pentahydroxyhexyl)-amino]-methyl}-phenyl)-acetamide(48):

[0226] The synthesis was carried out analogously to Example XVe),starting with 70 mg of4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-oneand 114 mg of(4-{[methyl-(2,3,4,5,6-pentahydroxyhexyl)-amino]-methyl}-phenyl)-aceticacid. This gave the product of molecular weight 747.84 (C41H47F2N3O8+);MS (ESI) 748.35 (M+H+). TABLE 1 Compounds of the formula I

Ex. R1, R2 R3, R4 XXIII

para-F, H XXIV

para-F, H XXV

para-F, H XXVI

para-F, H XXVII para-O-CH₃, H

XXVIII para-O-CH₃, H

XXIX

para-F, H XXX

para-F, H XXXI

para-F, H XXXII

para-F, H XXXIII

para-F, H XXXIV

para-F, H XXXV

para-F, H XXXVI para-O-CH₃, H

XXXVII para-O-CH₃, H

XXXVIII

para-F, H XXXIX

para-F, H XL para-O-CH₃, H

XLI para-O-CH₃, H

XLII para-O-CH₃, H

XLIII para-O-CH₃, H

XLIV para-O-CH₃, H

XLV para-O-CH₃, H

XLVI para-O-CH₃, H

XLVII para-O-CH₃, H

XLVIII para-O-CH₃, H

IL para-O-CH₃, H

L para-O-CH₃, H

LI para-O-CH₃, H

LII para-O-CH₃, H

LIII para-O-CH₃, H

LIV para-O-CH₃, H

LV para-O-CH₃, H

LVI

para-F, H LVII

para-F, H LVIII

para-F, H LIX

para-F, H LX para-O-CH₃, H

LXI para-O-CH₃, H

LXII para-O-CH₃, H

Molecular weight of the free base Molecular weight Ex. R5, R6 Salz oracid (calculated) (found) XXIII para-F, H Cl⁻ 651.78 651.31 (M⁺) XXIVpara-F, H CF₃COO⁻ 651.78 651.31 (M⁺) XXV para-F, H — 567.64 577.25 (MH⁺)XXVI para-F, H — 662.69 663.22 (MH⁺) XXVII para-F, H CF₃COOH 745.85746.34 (MH⁺) XXVIII para-F, H CF₃COOH 759.88 760.35 (MH⁺) XXIX para-F, H— 739.82 740 33 (MH⁺) XXX para-F, H CF₃COO⁻ 695.84 659.34 (M⁺) XXXIpara-F, H CF₃COO⁻ 709.86 709.35 (M⁺) XXXII para-F, H — 614.60 597.18(MH⁺-H₂O) XXXIII para-F, H — 620.65 621.24 (MH⁺) XXXIV para-F, H —606.65 607.32 (MH⁺) XXXV para-F, H CF₃COO⁻ 681.33 681.5 (M⁺) XXXVIpara-F, H Cl⁻ 755.92 755.36 (M⁺) XXXVII H, H — 615.71 616.21 (MH⁺)XXXVIII para-F, H CF₃COOH 554.65 555.20 (MH⁺) XXXIX para-F, H — 606.65607.39 (MH⁺) XL para-F, H Cl⁻ 775.95 775.40 (M⁺) XLI para-F, H Cl⁻699.85 699.33 (M⁺) XLII para-F, H HCl 651.74 652.38 (MH⁺) XLIII para-F,H Br⁻ 860.51 860.6 (M⁺) XLIV para-F, H — 595.67 596.38 (MH⁺) XLV para-F,H CF₃COOH 652.73 653.37 (MH⁺) XLVI para-F, H — 618.68 617.33 (M-H⁺;measured in negative mode XLVII para-F, H — 730.81 731.41 (MH⁺) XLVIIIpara-F, H — 672.76 655.28 (MH⁺-H₂O) IL para-F, H — 658.73 659.27 (MH⁺) Lpara-F, H — 710.78 693.25 (MH⁺-H₂O) LI para-F, H Cl⁻ 663.82 663.28 (M⁺)LII para-F, H — 588.68 589.34 (MH⁺) LIII para-F, H — 674.73 657.35(MH⁺-H₂O) LIV para-F, H — 633.70 615.70 (M⁺-H₂O) LV para-F, H Br 666.72666.33 (M⁺) LVI para,F, H Br 654.68 654.31 (M⁺) LVII para-F, H I⁻ 687.35687.4 (M⁺) LVIII para-F, H — 571.65 572.4 (MH⁺) LIX para-F, H — 621.66622.33 (MH⁺) LX para-F, H — 801.98 784.21 (M⁺-H₂O) LXI para-F, H —775.90 758.18 (M⁺-H₂O) LXII para-F, H — 882.04 883.49 (MH⁺)

[0227] Using the methods described below, the activity of the compoundsof the formula I according to the invention was examined:

[0228] Effect of the Compounds of the Invention on CholesterolAbsorption and 3H-taurocholic Acid Excretion Using Fecal Excrement ofMice, Rats or Hamsters

[0229] NMRI mice, Wistar rats, or Golden Syrian hamsters (in groups ofn=4-6) were kept in metabolic cages, where they were fed with a standarddiet (Altromin, Lage (Lippe)). The afternoon prior to the administrationof the radioactive tracers (14C-cholesterol), the feed was removed andthe animals were adapted to grates.

[0230] Additionally, the animals were labeled s.c. with 3H-TCA(taurocholic acid) (for example 1 μCi/mouse up to 5 μCi/rat) 24 hoursprior to the peroral administration of the test meal (14C-cholesterol inIntralipid® 20, Pharmacia-Upjohn).

[0231] Cholesterol absorption test: 0.25 ml/mouse Intralipid® 20(Pharmacia-Upjohn) ((spiked with 0.25 μCi of 14C-cholesterol in 0.1 mgof cholesterol) was administered perorally by gavage.

[0232] Test substances were prepared separately in 0.5% methylcellulose(Sigma)/5% Solutol (BASF, Ludwigshafen) or a suitable vehicle.

[0233] The administration volume of the test substance was 0.5 ml/mouse.The test substance was administered immediately prior to the test meal(Intralipid labeled with 14C-cholesterol) (cholesterol absorption test).

[0234] The feces were collected over a period of 24 h. Fecal eliminationof 14C-cholesterol and 3H-taurocholic acid (TCA) was determined after 24hours.

[0235] The livers were removed and homogenized, and aliquots wereincinerated in an oximate (Model 307, Packard) to determine the amountof 14C-cholesterol that had been taken up/absorbed.

[0236] Evaluation

[0237] Feces Samples

[0238] The total weight was determined, the sample was made up withwater to a defined volume and then homogenized, and an aliquot wasevaporated to dryness and incinerated in an oximate (Model 307 fromPackard for the incineration of radioactively labeled samples). Fheamount of radioactive ³H—H₂O and ¹⁴C—CO₂ was extrapolated to the amountof ³H-taurocholic acid and ¹⁴C-cholesterol, respectively, that wasexcreted (dual isotope technique). The ED₂₀₀ values were interpolatedfrom a dose-effect curve as those doses at which the excretion of TCA orcholesterol was doubled, based on a control group treated at the sametime.

[0239] Liver Samples

[0240] The amount of C-cholesterol taken up by the liver was based onthe administered dose. The ED50 values were interpolated from adose-effect curve as the dose at which the uptake of 14C-cholesterol bythe liver was halved (50% ), based on a control group.

[0241] The ED₅₀ values below demonstrate the activity of the compoundsof the formula I according to the invention Example No. ED₅₀ (liver)[mg/mouse] I <0.1 II <1.0 IV <0.1 V <0.1 VI 0.3 VII <1.0 VIII <1.0 IX<0.1 XV <1.0 XXIII 0.3 XXV 0.3 XXVI 0.1 XXVII 0.3 XXIX 0.3 XXXI 0.3XXXVI 0.03 XXXVII 0.1 XXXVIII 0.1 XLI 0.03 XLIII 0.3 XLIV 0.3 XLVI 0.3XLVIII 0.03 L 0.1 LII 0.3 LIII 0.03

[0242] As can be seen from the table, the compounds of the formula Ihave very good cholesterol-lowering action.

[0243] Bioabsorption

[0244] The bioabsorption of the compounds of the formula I was examinedusing the Caco cell model (A. R. Hilgers et al., Caco-2 cell monolayersas a model for drug transport across the intestinal mucosa, Pharm. Res.1990, 7, 902).

[0245] From the measured data, it can be seen that the bioabsorption ofthe compounds of the formula I according to the invention wasconsiderably lower than that of the compounds described in the prior art(reference structure):

Reference Structure:

[0246] Ezetimibe

We claim:
 1. A compound of the formula I,

wherein: R1, R2, R3, R4, R5, and R6, independently of one another, arechosen from: (C₁-C₃₀)-alkylene-(LAG)_(q), wherein at least one carbonatom of the alkylene radical is replaced by: aryl or heteroarylradicals, which are unsubstituted or substituted one, two, or threetimes by R7, or by (C₃-C₁₀)-cycloalkyl or heterocycloalkyl radicals,which are unsubstituted or substituted one, two, three, or four times byR7, and wherein at least one carbon atom of the alkylene radical isoptionally replaced by a radical chosen from: —S(O)_(m)— (where m=0-2),—O—, —(C═O)—, —(C═S)—, —CH═CH—, —C≡C—, —N((C₁-C₆)-alkyl)-, —N(phenyl),—N((C₁-C₆)-alkyl-phenyl)-, —N(CO—(CH₂)₁₋₁₀—COOH)— and —NH—; or H, F, Cl,Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)-alkyl, CONH₂,CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂C₆)-alkynyl, or O—(C₁-C₆)-alkyl, wherein the alkyl radical isunsubstituted or at least one hydrogen in the alkyl radical is replacedby fluorine; or SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂,S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl,SO—(CH₂)_(n)-phenyl, SO₂-(C₁-C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl; whereinn=0-6, and wherein the phenyl radical is unsubstituted or substitutedone or two times, each substituent chosen independently from: F, Cl, Br,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; or NH₂,NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NH(C₁-C₇)-acyl, phenyl, orO—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl ring isunsubstituted or substituted one, two, or three times, each substituentchosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; R7 represents F, Cl, Br, I,CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)-aikyl, CONH₂, CONH(C₁-C₆)-alkyl,CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, orO—(C₁-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at leastone hydrogen in the alkyl radical may be replaced by fluorine; or PO₃H₂,SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂,S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl,SO—(CH₂)_(n)-phenyl, SO₂—(C₁C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl, whereinn=0-6, and wherein the phenyl radical is unsubstituted or substitutedone or two times, each substituent chosen independently from: F, Cl, Br,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; orC(NH)(NH₂), NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NH(C₁-C₇)-acyl,phenyl, or O—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenylring is unsubstituted or substituted one, two, or three times, eachsubstituent chosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN,OCF₃, O—(C₁C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; (LAG) isa sugar residue, disugar residue, trisugar residue, tetrasugar residue;a sugar acid, an amino sugar; or an amino acid residue, or anoligopeptide residue comprising 2 to 9 amino acids; or an acyclic,mono-, di- or tricyclic trialkylammonium radical, an acyclic mono-, di-or tricyclic trialkylammoniumalkyl radical, —O—(SO₂)—OH;—(CH₂)₀₋₁₀—SO₃H, —(CH₂)₀₋₁₀—P(O)(OH)₂, —(CH₂)₀₋₁₀—O—P(O)(OH)₂,—(CH₂)₀₋₁₀COOH, —(CH₂)₀₋₁₀—C(═NH)(NH₂)′—(CH₂)₀₋₁₀—C(═NH)(NHOH),or—NR8-C(═NR9)(NR10R11); wherein q=1-5 and wherein R8, R9, R10 and R 11,independently of one another, are chosen from: H, (C₁-C₆)-alkyl, phenyl,(C₁-C₆)-alkyl-phenyl, and (C₃-C₈)-cycloalkyl, and wherein at least oneof the radicals R1 to R6 must have the meaning:(C₁-C₃₀)-alkylene-(LAG)_(q), wherein at least one carbon atom of thealkylene radical is replaced by: aryl or heteroaryl radicals, which areunsubstituted or substituted one, two, or three times by R7, or(C₃-C₁₀)-cycloalkyl or heterocycloalkyl radicals, which areunsubstituted or substituted one, two, three, or four times by R7, or—S(O)_(m)— (where m=0-2), —O—, —(C═O)—, —(C═S)—, —CH═CH—, —C≡C—,—N((C₁-C₆)-alkyl)-, —N(phenyl)-, —N((C₁-C₆)-alkyl-phenyl)-,—N(CO—(CH₂)₁₋₁₀—COOH)— or —NH—; or a pharmaceutically acceptable saltthereof, in any stereoisomeric form, or a mixture of any such compoundsin any ratio.
 2. A compound as claimed in claim 1, wherein R2, R4, R5,and R6, independently of one another, are chosen from: H, F, Cl, Br, I,CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, orO—(C₁-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at leastone hydrogen in the alkyl radical is replaced by fluorine; or SO₂—NH₂,SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl,S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl,SO₂—(C₁-C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl, wherein n=0-6, and whereinthe phenyl radical is unsubstituted or substituted one or two times,each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN,OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; or NH₂, NH—(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)₂, NH(C₁-C₇)-acyl, phenyl, or O—(CH₂)_(n)-phenyl,wherein n=0-6, and wherein the phenyl ring is unsubstituted orsubstituted one, two, or three times, each substituent chosenindependently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; R1 and R3, independently ofone another, are chosen from: (C₁-C₃₀)-alkylene-(LAG), wherein at leastone carbon atom of the alkylene radical is replaced by: aryl orheteroaryl radicals, which are unsubstituted or substituted one, two, orthree times by R7, or by (C₃-C₁₀)-cycloalkyl or heterocycloalkylradicals, which are unsubstituted or substituted one, two, or threetimes by R7 and wherein at least one carbon atom of the alkylene radicalis optionally replaced by a radical chosen from: —S(O)_(m)— (wherem=0-2), —O—, —(C═O)—, —N(CH₃)—, —N(phenyl)-, —N(CO—(CH₂)₁₋₁₀—COOH)— and—NH—, or H, F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)-alkyl,CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₂C₆)-alkynyl, or O—(C₁-C₆)-alkyl, wherein the alkylradical is unsubstituted or at least one hydrogen in the alkyl radicalis replaced by fluorine; or SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl,SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl,SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl, SO₂—(C₁-C₆)-alkyl, orSO₂—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl radical isunsubstituted or substituted one or two times, each substituent chosenindependently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, and NH₂; or NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,NH(C₁-C₇)-acyl, phenyl, or O—(CH₂)_(n)-phenyl, wherein n=0-6, andwherein the phenyl ring is unsubstituted or substituted one, two, orthree times, each substituent chosen independently from: F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C,C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl,and CONH₂; R7 represents F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH,COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, or O—(C₁-C₆)-alkyl,wherein the alkyl radical is unsubstituted or at least one hydrogen inthe alkyl radical is replaced by fluorine; or PO₃H₂, SO₃H, SO₂—NH₂,SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C,C₆)-alkyl,S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl,SO₂—(C₁C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl, wherein n=0-6, and whereinthe phenyl radical is unsubstituted or substituted one or two times,each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN,OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; or C(NH)(NH₂), NH₂,NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NH(C₁-C₇)-acyl, phenyl, orO—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl ring isunsubstituted or substituted one, two, or three times, each substituentchosen independently from: F. Cl, Br, I, OH, CF3, NO2, CN, OCF3,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; (LAG) is a sugar residue,disugar residue, trisugar residue, tetrasugar residue; a sugar acid, anamino sugar; or an amino acid residue, or an oligopeptide residuecomprising 2 to 9 amino acids; or an acyclic, mono-, di- or tricyclictrialkylammonium radical, an acyclic mono-, di- or tricyclictrialkylammoniumalkyl radical, —O—(SO₂)—OH; —(CH₂)₀₋₁₀—SO₃H,—(CH₂)₀₋₁₀—P(O)(OH)₂, —(CH₂)₀₋₁₀—O—P(O)(OH)₂, —(CH₂)₀₋₁₀COOH,—(CH₂)₀₋₁₀—C(═NH)(NH₂), —(CH₂)₀₋₁₀—C(═NH)(NHOH), or—NR8-C(═NR9)(NR10R11); wherein R8, R9, R10 and R11, independently of oneanother, are chosen from: H, (C₁-C₆)-alkyl, phenyl,(C₁-C₆)-alkyl-phenyl, and (C₃-C₈)-cycloalkyl), and wherein at least oneof the radicals R1 or R3 must have the meaning: (C₁-C₃₀)-alkylene-(LAG),wherein at least one carbon atom of the alkylene radical is replaced by:aryl or heteroaryl radicals, which are unsubstituted or substituted one,two, or three times by R7, or (C₃-C₁₀)-cycloalkyl or heterocycloalkylradicals, which are unsubstituted or substituted one, two, or threetimes by R7, or —S(O)_(m)— (where m=0-2), —O—, —(C═O)—, —N(CH₃)—,—N(phenyl)-, —N(CO—(CH₂)₁₋₁₀—COOH)— or —NH—; or a physiologicallyacceptable salt thereof, in any stereoisomeric form, or a mixture of anysuch compounds in any ratio.
 3. A compound as claimed in claim 1,wherein R2, R4, R5, and R6, independently of one another, are chosenfrom: H, F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)-alkyl, CONH₂,CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, or O—(C₁-C₆)-alkyl, wherein the alkyl radical isunsubstituted or at least one hydrogen in the alkyl radical is replacedby fluorine; or SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂,S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl,SO—(CH₂)_(n)-phenyl, SO₂—(C₁-C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl, whereinn=0-6, and wherein the phenyl radical is unsubstituted or substitutedone or two times, each substituent chosen independently from: F, Cl, Br,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; or NH₂,NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NH(C₁-C₇)-acyl, phenyl, orO—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl ring isunsubstituted or substituted one, two, or three times, each substituentchosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; R1 and R3, independently ofone another, are:—(CH₂)₀₋₁—NH—(C═O)₀₋₁—(C₀-C₂₅)-alkylene-(C═O)₀₋₁—N(R13)₀₋₁-(LAG) or—(CH₂)₀₋₁—(C═O)₀₋₁—NH—(C₀-C₂₅)-alkylene-(C═O)₀₋₁—N(R13)₀₋₁-(LAG);wherein at least one carbon atom of the alkylene radical is replaced by:aryl or heteroaryl radicals, which are unsubstituted or substituted one,two, or three times by R7, or by (C₃-C₁₀)-cycloalkyl or heterocycloalkylradicals, which are unsubstituted or substituted one, two, or threetimes by R7 and wherein at least one or more carbon atom of the alkyleneradical is optionally replaced by oxygen atoms; or H, F, Cl, Br, I, CF₃,NO₂, N₃, CN, COOH, COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂C₆)-alkynyl, orO—(C₁-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at leastone hydrogen in the alkyl radical is replaced by fluorine; or SO₂—NH₂,SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl,S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl,SO₂—(C₁-C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl, wherein n=0-6, and whereinthe phenyl radical is unsubstituted or substituted one or two times,each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN,OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; or NH₂, NH—(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)₂, NH(C₁-C₇)-acyl, phenyl, or O—(CH₂)_(n)-phenyl,wherein n=0-6, and wherein the phenyl ring is unsubstituted orsubstituted one, two, or three times, each substituent chosenindependently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; R7 represents F, Cl, Br, I,CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,CON[(C₁-C₆)-alkyl]2, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, orO—(C₁-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at leastone hydrogen in the alkyl radical is replaced by fluorine; or PO₃H₂,SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁C₆)-alkyl,S—(CH₂)₂-phenyl, SO—(C₁-C₆)-alkyl, SO—(CH₂),-phenyl, SO₂—(C₁C₆)-alkyl,or SO₂—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl radicalis unsubstituted or substituted one or two times, each substituentchosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; or C(NH)(NH₂), NH₂,NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NH(C₁-C₇)-acyl, phenyl, orO—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl ring isunsubstituted or substituted one, two, or three times, each substituentchosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; (LAG) is a sugar residue,disugar residue, trisugar residue, tetrasugar residue; a sugar acid, anamino sugar; or an amino acid residue, or an oligopeptide residuecomprising 2 to 9 amino acids; or an acyclic, mono-, di- or tricyclictrialkylammonium radical, an acyclic mono-, di- or tricyclictrialkylammoniumalkyl radical, —O—(SO₂)—OH; —(CH₂)₀₋₁₀—SO₃H,—(CH₂)₀₋₁₀—P(O)(OH)₂, —(CH₂)₀₋₁₀-O—P(O)(OH)₂, —(CH₂)₀₋₁₀—COOH,—(CH₂)₀₋₁₀—C(═NH)(NH₂), —(CH₂)₀₋₁₀—C(═NH)(NHOH), or—NR8-C(═NR9)(NR10R11); wherein q=1-5 and wherein R8, R9, R10 and R11,independently of one another, are chosen from: H, (C₁-C₆)-alkyl, phenyl,(C₁-C₆)-alkyl-phenyl, and (C₃-C₈)-cycloalkyl), R13 represents H or CH₃;and wherein at least one of the radicals R1 or R3 must have the meaning:—(CH₂)₀₋₁—NH—(C═O)₀₋₁—(C₀-C₂₅)-alkylene-(C═O)₀₋₁—N(R13)₀₋₁-(LAG) or—(CH₂)₀₋₁—(C═O)₀₋₁—NH—(C₀-C₂₅)-alkylene-(C═O)₀₋₁—N(R13)₀₋₁-(LAG),wherein at least one carbon atom of the alkylene radical is replaced by:aryl or heteroaryl radicals, which are unsubstituted or substituted one,two, or three times by R7, or (C₃-C₁₀)-cycloalkyl or heterocycloalkylradicals, which are unsubstituted or substituted one, two, or threetimes by R7, or —S(O)_(m)— (where m=0-2), —O—, —(C═O)—, —N(CH₃)—,—N(phenyl)- or —NH—; or a physiologically acceptable salt thereof, inany stereoisomeric form, or a mixture of any such compounds in anyratio.
 4. A compound as claimed in claim 1, wherein LAG is chosen from:a monosugar residue, an acyclic mono-, di- or tricyclictrialkylammoniumalkyl radical, a sulfonic acid and a carboxylic acid, ora pharmaceutically acceptable salt thereof, in any stereoisomeric form,or a mixture of any such compounds in any ratio.
 5. A pharmaceuticalcomposition, comprising an effective amount of at least one compound asclaimed in claim
 1. 6. A pharmaceutical composition, comprising aneffective amount of at least one compound as claimed in claim 1 and atleast one additional active compound.
 7. The pharmaceutical compositionof claim 6, wherein the at least one additional active compound ischosen from compounds that normalize lipid metabolism.
 8. Thepharmaceutical composition of claim 6, wherein the at least oneadditional active compound is chosen from antidiabetics,hypoglycemically active compounds, HMGCoA reductase inhibitors,cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alphaagonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acidabsorption inhibitors, CETP inhibitors, polymeric bile acid adsorbers,LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipaseinhibitors, ATP citrate lyase inhibitors, squalene synthetaseinhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins,sulfonylureas, biguanides, meglitinides, thiazolidinediones,α-glucosidase inhibitors, active compounds which act on theATP-dependent potassium channel of the beta cells, CART agonists, NPYagonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRFagonists, CRF BP antagonists, urocortin agonists, β3 agonists, MSH(melanocyte-stimulating hormone) agonists, CCK agonists,serotonin-reuptake inhibitors, mixed serotonin and noradrenergiccompounds, 5HT agonists, bombesin agonists, galanin antagonists, growthhormones, growth hormone-releasing compounds, TRH agonists, decouplingprotein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine,doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators orTR-β-agonists and amphetamines.
 9. A method for treating impaired lipidmetabolism, comprising administering to a patient in need thereof aneffective amount of at least one compound as claimed in claim
 1. 10. Aprocess for preparing a pharmaceutical composition comprising at leastone compound as claimed in claim 1, comprising mixing the at least onecompound with a pharmaceutically acceptable carrier and bringing thismixture into a form suitable for administration.
 11. A method fortreating hyperlipidemia, comprising administering to a patient in needthereof an effective amount of at least one compound as claimed inclaim
 1. 12. A method for lowering the serum cholesterol concentrationof a patient, comprising administering to a patient in need thereof aneffective amount of at least one compound as claimed in claim
 1. 13. Amethod for treating arteriosclerotic manifestations, comprisingadministering to a patient in need thereof an effective amount of atleast one compound as claimed in claim
 1. 14. A method for treatinginsulin resistance, comprising administering to a patient in needthereof an effective amount of at least one compound as claimed in claim1.